Trichothiodystrophy

Abstract

Trichothiodystrophy (TTD) is a rare autosomal recessive multisystem disorder characterized by hair abnormalities and a wide spectrum of clinical manifestations including physical and mental retardation, ichthyosis, proneness to infections, signs of premature ageing and, in about half of the reported cases, cutaneous photosensitivity. Both the photosensitive and the non-photosensitive form of TTD show similar clinical outcome and include patients who differ in type and severity of symptoms. Here we discuss the cellular and genetic defects associated with TTD, the functions of the disease genes identified so far and the genotype-phenotype relationships. The three genes responsible for the photosensitive form of TTD encode distinct subunits of the general transcription factor TFIIH, which plays a key role also in DNA repair. Subtle defects in transcription can easily explain the spectrum of TTD clinical symptoms except for clinical and cellular photosensitivity that, however, in TTD does not result in increased carcinogenesis. The recent finding that alterations in the β-subunit of the basal transcription factor TFIIE result in the non-photosensitive form of TTD highlights the relevance of transcriptional alterations for the TTD pathological phenotype. Besides reporting recent research advances, we discuss how alterations in distinct pathways may result in specific TTD clinical manifestations, namely, cutaneous photosensitivity, lack of skin cancer, ageing signs and neurological alterations.